Design, synthesis, and biological evaluation of novel aminobisphosphonates possessing an in vivo antitumor activity through a gammadelta-T lymphocytes-mediated activation mechanism.
A small series of aminobisphosphonates (N-BPs) structurally related to zoledronic acid was synthesized with the aim of improving activity toward activation of human gammadelta T cells and in turn their in vivo antitumor activity. The absence of the 1-OH moiety, together with the position and the different basicity of the nitrogen, appears crucial for antitumor activity. In comparison to zoledronic acid, compound 6a shows a greater ability to activate gammadelta T cells expression (100 times more) and a proapoptotic effect that is better than zoledronic acid. The potent activation of gammadelta T cells, in addition to evidence of the in vivo antitumor activity of 6a, suggests it may be a new potential drug candidate for cancer treatment.
Simoni
Daniele
D
Dipartimento di Scienze Farmaceutiche, Universita di Ferrara, Italy. smd@unife.it
Gebbia
Nicola
N
Invidiata
Francesco Paolo
FP
Eleopra
Marco
M
Marchetti
Paolo
P
Rondanin
Riccardo
R
Baruchello
Riccardo
R
Provera
Stefano
S
Marchioro
Carla
C
Tolomeo
Manlio
M
Marinelli
Luciana
L
Limongelli
Vittorio
V
Novellino
Ettore
E
Kwaasi
Aaron
A
Dunford
James
J
Buccheri
Simona
S
Caccamo
Nadia
N
Dieli
Francesco
F
D000588:Amines / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D015394:Molecular Structure; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D013329:Structure-Activity Relationship
D000588:Amines; D000970:Antineoplastic Agents; D004164:Diphosphonates; D016692:Receptors, Antigen, T-Cell, gamma-delta